Hydrophilic high quantum yield acridinium esters with improved stability and fast light emission

a technology of acridinium esters and acridinium esters, which is applied in the field of hydrophilic, high quantum yield, chemiluminescent acridinium compounds, can solve the problems of limiting commercial utility, and achieve the effects of improving stability, high quantum yield and increasing light outpu

Active Publication Date: 2020-06-18
SIEMENS HEALTHCARE DIAGNOSTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]It has surprisingly been found that hydrophilic, high quantum yield, chemiluminescent acridinium esters possessing electron-donating functional groups of the form —OG at C2 and / or C7 of the acridinium ring, where G represents a branched hydrophilic substituent, provide increased light output, improved stability, fast light emission and / or low non-specific binding in assays.

Problems solved by technology

However, this acridinium ester is quite unstable, thereby limiting its commercial utility.
This instability arises from hydrolysis of the 9-carboxyphenyl ester linkage between the phenol and the acridinium ring.

Method used

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  • Hydrophilic high quantum yield acridinium esters with improved stability and fast light emission
  • Hydrophilic high quantum yield acridinium esters with improved stability and fast light emission
  • Hydrophilic high quantum yield acridinium esters with improved stability and fast light emission

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of B1-AE-NHS ester, 1i

a) 1,3-Bis(methoxyethoxy)-2-propyl toluenesulfonate, 1b

[0106]The compound 1a, 1,3-bis(methoxyethoxy)-2-propanol was synthesized as described by Cormier and Gregg in Chem. Mater. 1998, 10, 1309-1319. A solution of 1a (2 g, 9.6 mmol) in anhydrous pyridine (10 mL) was treated with 4-dimethylaminopyridine (0.234 g, 1.92 mmol) followed by p-toluenesulfonyl chloride (3.67 g, 19.25 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 days. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate (75 mL) and 10% HCl (100 mL). The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product (4.05 g) was purified by flash chromatography on silica gel using 1:1, ethyl acetate / hexanes as eluent. The product was recovered as a light yellow oil. Yield=2.42 g (70%).

b) Compound 1d

[0107]A mixture of 2,7-dihyd...

example 2

Synthesis of B2-AE-NHS ester, 2h

a). 1,3-Bis(3,6-dioxaheptanyl)glycerol-2-toluenesulfonate, 2b

[0112]The compound 1,3-Bis(3,6-dioxaheptanyl)glycerol, 2a, was synthesized as described by Vacus and Simon in Adv. Mater. 1995, 7, 797-800. Crude 2a (16 g, 0.054 mol) was dissolved in anhydrous pyridine (50 mL) and treated with 4-dimethylaminopyridine (1.32 g, 0.011 mol) followed by p-toluenesulfonyl chloride (12.4 g, 0.065 mol). The reaction was stirred under a nitrogen atmosphere for 16 hours. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and 2N HCl (100 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate solution followed by brine. It was then dried over magnesium sulfate and concentrated under reduced pressure. The crude product (14 g) was purified by flash chromatography on silica gel using 1:4, hexanes / ethyl acetate as eluent. Yield=6.3 g, light yellow oil. MALDI-TOF MS 473.4 observed, (M+Na+).

b)...

example 3

B3-AE-NHS ester 3h

a) 1,3-Bis(3,6,9-dioxadecanyl)glycerol-2-toluenesulfonate, 3b

[0119]The compound 1,3-Bis(3,6,9-dioxadecanyl)glycerol, 3a, was synthesized as described by Lauter et al. in Macromol. Chem. Phys. 1998, 199, 2129-2140. The alcohol (7 g, 0.0182 mol) was dissolved in anhydrous pyridine (30 mL) and treated with 4-dimethylaminopyridine (0.444 g, 3.6 mmol) and p-toluenesulfonyl chloride (3.85 g, 0.02 mol). The reaction was stirred under a nitrogen atmosphere for 3 days. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and 10% HCl (100 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine. It was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 5:4.5:0.5, hexanes:ethyl acetate:methanol. Yield=4.47 g (45%); light yellow oil.

b) Compound 3c

[0120]A mixture of 1c (0.2 ...

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Abstract

Hydrophilic, high quantum yield, chemiluminescent acridinium compounds with increased light output, improved stability, fast light emission and decreased non specific binding are disclosed. The chemiluminescent acridinium esters possess hydrophilic, branched, electron-donating functional groups at the C2 and / or C7 positions of the acridinium nucleus.

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 843,528 filed Jul. 8, 2013, which is incorporated herein by reference in its entirety.2. FIELD OF THE INVENTION[0002]The present invention relates to hydrophilic, high quantum yield, chemiluminescent acridinium compounds with increased light output, improved stability, fast light emission and low non-specific binding. These compounds because of their enhanced quantum yield and hydrophilic nature, are useful in improving assay sensitivity. The improved stability of these compounds is useful for extending the shelf life of reagents using these compounds as well as for minimizing variation in assay performance with time. Their increased emission kinetics also permits faster light measurements in assays especially in automated analyzers.3. BACKGROUND OF THE INVENTION[0003]Chemiluminescent acridinium esters (AEs) are extremely useful labels that have been used exte...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D219/06C09K11/07G01N33/58F21K2/06G01N21/76
CPCG01N21/76F21K2/06C07D219/06C09K11/07G01N33/582G01N33/543
Inventor NATRAJAN, ANANDSHARPE, DAVIDJIANG, QINGPINGWEN, DAVID
Owner SIEMENS HEALTHCARE DIAGNOSTICS INC
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